Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors

  • Bioorg Med Chem Lett. 2009 Aug 1;19(15):4034-41. doi: 10.1016/j.bmcl.2009.06.014.
Yan Shi  1 ,  Jing Zhang ,  Mengxiao Shi ,  Stephen P O'Connor ,  Sharon N Bisaha ,  Chi Li ,  Doree Sitkoff ,  Andrew T Pudzianowski ,  Saeho Chong ,  Herbert E Klei ,  Kevin Kish ,  Joseph Yanchunas Jr ,  Eddie C-K Liu ,  Karen S Hartl ,  Steve M Seiler ,  Thomas E Steinbacher ,  William A Schumacher ,  Karnail S Atwal ,  Philip D Stein
Affiliations
  • 1. Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. [email protected]
PMID: 19541481 DOI: 10.1016/j.bmcl.2009.06.014
Abstract

The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.

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